A comparison of the safety and efficacy of alprazolam and desipramine in moderately severe depression

Fifty-four patients (34 outpatients, 20 inpatients) fulfilling Research Diagnostic Criteria for Definite Major Depressive Disorder were enrolled in a double-blind study comparing the antidepressant effects of alprazolam versus desipramine. The mean daily dose of alprazolam and desipramine at study termination was 3.78 mg and 208 mg respectively. As there were no significant demographic or clinical differences between outpatients and inpatients, both groups were combined in data analysis. Using the Hamilton Depression Rating Scale (HAM-D) both drug groups showed highly significant improvement beginning with the first week of active drug treatment. HAM-D scores continued to decrease through study termination (six weeks of active drug). There were no significant differences when comparing alprazolam and desipramine (outpatients, inpatients, or both groups combined) on any of the subjective or objective psychometrics used in this study. Clinically, only twelve of thirty-four outpatients (35.3%) were felt to be "markedly or moderately" improved, suggesting that neither the outpatient alprazolam nor desipramine patients did particularly well with drug treatment. In terms of drug safety there was no difference between the alprazolam and desipramine in the number of excessive or serious drug side effects. However, five of twenty-nine alprazolam patients had to discontinue therapy because of excessive drowsiness, and two of the alprazolam outpatients had motor vehicle accidents directly related to this adverse event. Alprazolam appeared as effective as desipramine in the pharmacotherapy of this group of depressed outpatient and inpatients. Alprazolam appeared well-tolerated by most subjects although drowsiness was a common--and at times serious--medication side effect.     

Treatment of bulimia with desipramine: a double-blind crossover study

The purpose of this study was to evaluate the effect of desipramine, a tricyclic antidepressant with relatively specific noradrenergic effects, on bulimic behaviour, eating attitudes, and mood. Using a double-blind crossover design, 47 normal weight bulimics were randomly assigned to receive either desipramine (150 mg/day) for six weeks, no drug for three weeks, followed by placebo for six weeks, or the reverse sequence. At weeks 0, 2, 4, 6, 9, 11, 13, and 15, each subject was assessed using the EDI, SCL-90, POMS and binge records. Plasma desipramine levels were obtained at weeks 4 and 13. Twenty-four subjects completed the entire fifteen week protocol, while 23 dropped out. Desipramine was significantly more effective than placebo in reducing the frequency of weekly binding, weekly vomiting, and the fatigue scale of the POMS. No significant effect of the drug was obtained on the EDI or the SCL-90. The clinical effect was modest. Desipramine's antibulimic effects were not associated with an alleviation of depressive symptoms.     

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety

In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.     

A double blind comparison of alprazolam and amitriptyline hydrochloride in the treatment of nonpsychotic depression

In a six week, double-blind, parallel study of alprazolam and amitriptyline hydrochloride in 130 outpatients suffering from moderate to severe nonpsychotic depression, alprazolam was as effective as amitriptyline hydrochloride in relieving depressive symptoms and significantly more effective in relieving symptoms of anxiety and somatization. Alprazolam showed an earlier onset of activity in most measurements of efficacy and produced fewer side effects than amitriptyline hydrochloride. Anticholinergic side effects were reported more frequently by patients taking amitriptyline hydrochloride, while drowsiness was reported more frequently by patients taking alprazolam. At the end of the study, the average daily doses were 2.4 mg alprazolam and 135 mg amitriptyline hydrochloride. The Hamilton Psychiatric Rating Scale for Depression, Hamilton Anxiety Rating Scale, Physician's Global Impressions, Patients' Global Impressions, Hopkins Self-Rating Symptom Scale, and Symptom and Side Effects Checklist were evaluated at the end of weeks 1, 2, 3 and 6 to determine and compare the efficacy and safety of the two study drugs.     

Comparison between zimelidine and desipramine in endogenous depression. A cross-over study

Depressed patients, who did not respond after 4 weeks treatment with zimelidine 100 mg b.i.d. (five patients) or desipramine 75 mg b.i.d. (11 patients) in a double-blind randomized study were crossed over, after 1 placebo week, to 4 weeks of treatment with the other drug. The three zimelidine non-responders who responded to desipramine were significantly more retarded compared with eight desipramine non-responders who responded to zimelidine. It was observed that two patients with bipolar depression developed mania during crossover treatment with desipramine, while two patients with bipolar depression who were treated with zimelidine during the second treatment period did not show any symptoms of mania. Three patients who were non-responders during both treatment periods had lower plasma concentration of the drugs compared with respective responding groups.     

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects

Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication. In this study, 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks. The medication was tapered over a period of four weeks, and patients were observed for another two weeks after all medication was discontinued. Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study. After improvement in the active treatment period, the alprazolam-treated group had significant relapse between the first and last week of taper. However, during the second postdiscontinuation week, outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper. Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13% reported a rebound of anxiety on the Hamilton Anxiety Scale. No serious or life-threatening withdrawal symptoms were reported, but distinct, transient, mild to moderate withdrawal syndrome occurred in 35% of the alprazolam-treated group and in none of the placebo-treated group. The coexistence of symptom rebound and a withdrawal syndrome occurred in 10% of the alprazolam-treated group, but both subsided by the end of the second week without alprazolam. We recommend that patients with panic disorder be treated for a longer period, at least six months, and that medication be tapered over a more prolonged period, at least eight weeks, especially where high doses are employed.     

Alprazolam effects in children with anxiety disorders

Children with overanxious and/or avoidant disorder (DSM-III) were treated with alprazolam (Xanax, Upjohn) to determine its safety, clinical and cognitive effects. Ten male and two female patients (age range 8.8 to 16.5 years; mean 11.5) participated in an open clinical trial consisting of a baseline placebo period (1 week), alprazolam therapy (4 weeks), a drug-tapering period (1 week), and a post-drug placebo period (1 week). There was a drug-free follow-up approximately 4 weeks after termination of the study. Dosages were individually adjusted and the daily maximum ranged from 0.50 mg to 1.5 mg. Evaluations included clinical assessments, parent, teacher and self ratings, and cognitive tests. Clinical global improvement with alprazolam therapy was marked in 1 patient, moderate in 6, minimal in 4, and none in 1. Clinician ratings indicated significant improvements of anxiety, depression, and psychomotor excitation. Parent questionnaires indicated significant improvements of anxiety and hyperactivity while teacher questionnaires showed significant improvement of an anxious-passive factor. Significant improvements in the paired associate learning tasks, maze task and the block design tasks were maintained after drug withdrawal suggesting a practice effect. Adverse effects were infrequent, mild and transient. There were no clinically significant changes of laboratory values, blood pressure, pulse or respiration during the 4 weeks of alprazolam administration. Body weight increased significantly (mean increase was 0.87 kg). Double-blind trials with alprazolam are recommended in child psychiatry disorders.     

Bulimia: independence of antibulimic and antidepressant properties of desipramine

The purpose of this study was to identify variables useful for predicting a positive response to the tricyclic antidepressant desipramine, amongst bulimic subjects. Using a randomized double-blind cross-over design, 24 normal weight bulimics completed a 15-week protocol in which they received either desipramine (150 mg/day) for six weeks, no drug for three weeks, followed by placebo for six weeks, or the reverse sequence. At weeks 0, 2, 4, 6, 9, 11, 13, and 15, each subject was assessed using the EDI, SCL-90, POMS and binge records. The DST, Diagnostic Interview Schedule (DIS), and a personal and family medical-psychiatric history questionnaire were administered at initial assessment, while plasma desipramine levels were obtained at weeks 4 and 13. Responders were defined in terms of both binge frequency reduction, and decrease in depressive symptoms. In the sample of 24 subjects, desipramine was significantly more effective than placebo in reducing the frequency of weekly binging and vomiting, as well as causing a reduction in the fatigue scale of the POMS. No significant effect of the drug was obtained on the EDI or the SCL-90. In terms of reduction in binge frequency, seven responders were identified; another seven were found to be borderline responders, while 10 were labeled as non-responders. The three groups did not differ in terms of their initial scores on the SCL-90, POMS, DST, DIS results, or psychological subscales of the EDI. However, responders were found to have lower EDI bulimia subscale scores, but a higher frequency of purging episodes than were non-responders. Eight patients were identified as borderline responders with respect to depressive symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam

BACKGROUND: Pregabalin inhibits release of excess excitatory neurotransmitters, presumably by binding to the alpha2-delta subunit protein of widely distributed voltage-dependent calcium channels in the brain and spinal cord. OBJECTIVE: To assess the anxiolytic efficacy of pregabalin in patients with generalized anxiety disorder. DESIGN: Double-blind, placebo-controlled, active-comparator trial. Patients were randomized to 4 weeks of treatment with pregabalin, 300 mg/d (n = 91), 450 mg/d (n = 90), or 600 mg/d (n = 89); alprazolam, 1.5 mg/d (n = 93); or placebo (n = 91). SETTING: Psychiatry research and clinic settings. PATIENTS: Outpatients meeting the DSM-IV criteria for generalized anxiety disorder, with a baseline Hamilton Anxiety Rating Scale (HAM-A) total score of 20 or greater. MAIN OUTCOME MEASURES: Change from baseline to end point in total HAM-A score in the pregabalin and alprazolam groups compared with the placebo group. The end point response criterion was 50% or greater reduction in the HAM-A total score. RESULTS: Pregabalin and alprazolam produced a significantly greater reduction in mean +/- SE HAM-A total score at last-observation-carried-forward end point compared with placebo (-8.4 +/- 0.8): pregabalin, 300 mg (-12.2 +/- 0.8, P<.001), 450 mg (-11.0 +/- 0.8, P = .02), and 600 mg (-11.8 +/- 0.8, P = .002), and alprazolam (-10.9 +/- 0.8, P = .02). By week 1 and at last-observation-carried-forward end point, the 3 pregabalin groups and the alprazolam group had significantly (P<.01) improved HAM-A psychic anxiety symptoms compared with the placebo group. Compared with the placebo group, HAM-A somatic anxiety symptoms were also significantly (P<.02) improved by the 300- and 600-mg pregabalin groups, but not by the 450-mg pregabalin (week 1, P = .06; week 4, P = .32) and the alprazolam groups (week 1, P = .21; week 4, P = .15). Of the 5 treatment groups, the 300-mg pregabalin group was the only medication group that differed statistically in global improvement at treatment end point not only from the placebo group but also from the alprazolam group. CONCLUSION: Pregabalin was significantly more efficacious than placebo for the treatment of psychic and somatic symptoms of generalized anxiety disorder and was well tolerated by most study patients.     

Clinical comparison between alprazolam and lorazepam. A polycentric study in double blind

The clinical efficacy and safety of alprazolam was compared to lorazepam in a double blind randomized design involving 82 out-patients suffering from primary anxiety. Seventy four patients (37 on alprazolam and 37 on lorazepam) were evaluable. They were treated with a flexible dose of 0,75 mg to 3 mg of alprazolam per day (average final dose: 1,59 mg) or 3 mg to 12 mg of lorazepam per day (average final dose: 5,97 mg). The results show that the two drugs produce similar efficacious effects at weeks 2 and 4 of the treatment as evaluated using both patient and physician scales. At week 1, as could be expected from an average daily dose of 0,99 mg of alprazolam and of 4,14 mg of lorazepam, efficacy parameters favored lorazepam. Fifty seven side effects were reported in the 37 lorazepam patients while 61 side effects were reported in the 37 alprazolam patients.     

Lithium carbonate augmentation of desipramine in refractory depression

An open clinical study with 20 consecutive outpatients suffering from major depression with melancholia (DSM-III) was carried out. All patients were resistant to desipramine after at least six weeks of treatment. A significant improvement was found in 13 of the 20 patients when lithium carbonate was added. Among the responder patients, five improved in the first week of lithium augmentation, while eight others improved after one week of lithium. The mechanism of action of the lithium augmentation effect in tricyclic-resistant depressed patients is discussed in view of our findings. We suggest that the unified 5-HT/NE hypothesis used in affective disorder could be applied in drug refractory depression.     

Antidepressant effect of femoxetine and desipramine and relationship to the concentration of amine metabolites in cerebrospinal fluid

The antidepressant and biochemical effects of femoxetine, a selective serotonin uptake inhibitor, and desipramine, a selective nor-adrenaline uptake inhibitor, have been compared in a double–blind study in 42 outpatients with depressive illness. The patients were allocated at random to treatment with either 600 mg femoxetine or 150 mg desipramine daily for 6 weeks. The total depression score showed a significant decrease in both groups, indicating an overall improvement in depressive symptoms. The patients treated with femoxetine reported significantly less severe anticholinergic effects during the whole treatment period than the desipramine patients. Both drugs decreased the level of 5-HIAA in CSF, whereas no consistent changes were found in the HMPG and HVA levels. The pretreatment level of the metabolites had no predictive value for the outcome of the treatment with either drug. No significant correlation was found between therapeutic effect and the plasma concentration of the active compounds.     

Double-blind comparison of alprazolam, diazepam, and placebo for the treatment of negative schizophrenic symptoms

Fifty-five schizophrenic outpatients with negative symptoms were treated for up to six weeks by the addition of alprazolam (mean dose, 4.2 mg/d), diazepam (mean dose, 40.4 mg/d), or placebo to their ongoing neuroleptic treatment. A repeated-measures analysis of variance with baseline measurements entered as covariates indicated the presence of a significant time X drug interaction effect for the weekly Brief Psychiatric Rating Scale (BPRS) withdrawal/retardation subfactor scores. During the initial weeks of the study, the alprazolam-treated group had lower scores, while the diazepam-treated group had higher scores than the placebo-treated group. However, an end point analysis performed on the final BPRS withdrawal/retardation subfactor scores showed no significant differences among the three groups, nor were beneficial effects observed on any of the BPRS subfactor scores that assess positive symptoms. Plasma alprazolam levels were maintained throughout the study and ranged from 20 to 100 ng/mL. These results suggest that alprazolam had no sustained significant effect on negative schizophrenic symptoms.     

Comparison of the serum levels in primary non-agitated depressed out-patients treated with imipramine in combination with placebo, diazepam or dixyrazine

Sixty-three non-agitated depressed out-patients were selected according to the Feighner-Robins-Guze criteria for primary depressions for a double-blind, between-patient randomized study for an 8 week duration. All the patients were treated with imipramine following a fixed dose schedule for the first 2 weeks and thereafter according to clinical response (100-200 mg/day). This treatment was combined with either placebo, diazepam (10 mg/day) or dixyrazine (50 mg/day). The serum concentration of imipramine both at 2 weeks and later was significantly higher (P less than 0.05) in the group treated with dixyrazine than in the other two groups. In the group treated with diazepam, the serum levels of imipramine and desipramine were significantly lower than in the placebo group. The serum concentrations of diazepam, desmethyldiazepam and dixyrazine were almost unchanged during the study. No significant correlation was found between the dosage and the serum concentration of imipramine or desipramine. The change in mean CPRS-score correlated neither with the imipramine nor with the desipramine serum levels, it did correlate but negatively with the degree of side effects. The degree of side effects correlated positively with the serum concentration of desipramine.     

Lorazepam vs. alprazolam in the treatment of panic disorder

Sixty-seven patients with panic disorder were treated with single-blind placebo for one week before being randomized to 6 weeks of double-blind treatment with either lorazepam or alprazolam. Both drugs showed significant and comparable antipanic efficacy throughout the course of the study. With the exception of sedative effects, both drugs were well-tolerated at a mean daily dose of 7 mg for lorazepam and 3 mg for alprazolam. Lorazepam appeared to be as effective as alprazolam in the acute treatment of panic disorder.     

Neuroleptic dose and desipramine concentrations during combined treatment of unipolar delusional depression

The relationship of response to neuroleptic dose and desipramine plasma concentration was examined in 31 patients with unipolar delusional depression. The patients received either perphenazine or haloperidol for 1-2 weeks, after which desipramine, 2.5 mg/kg of body weight per day, was added. Neuroleptic dose varied among patients but was constant within individuals. Global response was rated retrospectively on the basis of outcome during the fourth week of combined drug treatment. Responders had higher plasma desipramine concentrations and had received higher neuroleptic doses than nonresponders had. The effective threshold level for desipramine was similar to that previously described for nonpsychotic melancholic patients, suggesting a similar mode of action for the drug in the two disorders.     

A double-blind comparison of fluvoxamine, desipramine and placebo in outpatients with depression

Deborah Roth, Jeffrey Mattes, K. Harnett Sheehan and David V. Sheehan: A Double-Blind Comparison of Fluvoxamine, Desipramine and Placebo in Outpatients with Depression. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, : 929–939.

1. 1. The efficacy of fluvoxamine is compared to that of desipramine in a multicenter double blind placebo controlled six-week flexible dose trial of 90 outpatients with major depressive disorder.

2. 2. Although overall drug effects were relatively weak, there were trends suggesting separation of both active drugs from placebo at week six. Both drugs were well tolerated.

3. 3. Studies of major depression ought to be designed to last 8–10 weeks in order to demonstrate placebo active drug differences and the stability of such a difference should it occur in the first six weeks.

Patterns of plasma imipramine-desipramine concentrations in patients receiving concomitant fluphenazine decanoate

Plasma levels of imipramine and desipramine were monitored in a series of 13 patients with postpsychotic depressions who had a fixed dose of imipramine (150 mg/day) added to their clinically adjusted, stable dose of fluphenazine decanoate. Despite the potential for metabolic inhibition of the tricyclic drug by the neuroleptic drug, no relationship was found between the fluphenazine dose and the subsequent plasma concentrations of imipramine and desipramine. However, plasma antidepressant levels after 1 week at a low dose (50 mg/day) identified patients who later generated high plasma antidepressant levels at the full antidepressant dosage. The clinical implications of these observations are discussed.     

万拉法新联合阿普唑仑治疗抑郁症伴焦虑症状的疗效对照分析

目的　观察万拉法新联合阿普唑仑和单独氟西汀治疗抑郁症伴焦虑症状的临床疗效。方法　将符合入组条件的 6 2例患者分为两组 ,分别给予万拉法新联合阿普唑仑和单独氟西汀治疗 ,分别于治疗前及治疗 1、2、4、6周使用汉密尔顿抑郁量表 (HAMD)、汉密尔顿焦虑量表 (HAMA)、临床总体印象量表 (CGI)、不良反应量表(TESS)进行评分。结果　两组HAMD减分率第 1、2周末有显著性差异 (P <0 0 5 )和非常显著性差异 (P <0 0 1) ,HAMA减分率第 1、2、4周末有非常显著性差异 (P <0 0 1)和显著性差异 (P <0 0 5 ) ,CGI评定第 1周末两组有显著性差异 (P <0 0 5 )。结论　万拉法新联合阿普唑仑是一种疗效好、起效快而安全的治疗抑郁症伴焦虑症状的用药模式     

Drug treatment of panic disorder: the comparative efficacy of imipramine, alprazolam, and trazodone

Data from 74 patients with panic disorder were evaluated to determine the comparative efficacy of imipramine, alprazolam, and trazodone. All patients were treated with placebo for 3 weeks and were then blindly switched to active treatment for 8 weeks. Both imipramine and alprazolam were highly effective in reducing the symptoms of generalized anxiety, the frequency of panic attacks, and phobic avoidance. However, the time course of these effects differed; alprazolam demonstrated therapeutic properties during the first week, whereas the therapeutic efficacy of imipramine was not clearly apparent until the fourth week of treatment. Relative to imipramine and alprazolam, trazodone was not an effective treatment for panic disorder and was poorly tolerated; only 17 trazodone-treated patients completed at least 4 weeks of treatment, and only 2 patients were considered good or complete responders. These findings support the hypotheses that drugs that are efficacious in the treatment of panic disorders act by altering noradrenergic function and that drugs with primary actions on serotonin function are likely to be less effective treatments. The different time courses of therapeutic action of imipramine and alprazolam indicate that these drugs ameliorate panic anxiety via different mechanisms. The possible therapeutic applications of this observation are discussed.